It is known that enkaphalin or endorphine as the analgesic peptide exists in the brain of mammalian animals and particularly enkaphalin is existing at a high level in the vesicles of the nervous cells at the nerve ending of the nerve fibre in the brain, and also that enkephalinase is co-existing in the same areas as those where the enkephalin is found. Besides, the possibility that enkaphalin functions as neurotransmitters in the central nervous system of mammalian animals is suggested in the "Nature" Vol. 276, pages 523 to 526 (1980).
Furthermore, it has been revealed that acupuncture analgesia is mediated through release of the analgesic peptides such as enkephalin in the brain when the effectiveness of acupuncture analgesia was examined by measuring tail-flick latency of rats while the contents of the analgesic peptides in the brain were determined (see the Japanese medicinal Journal "Showa Igakukai Zasshi" Vol. 39, No. 5, pages 537 to 542 (1979). It is also reported that the analgesic activity of morphine is relying on that morphine plays a role to cause enkephalin to be released in the nervous system (see the "Life Science" No.25, pages 53 to 60 (1979)).
We have taken the above facts into consideration and we take it that generally, an inhibitor against enkephalinase will show an analgesic activity when it is used alone and it is expected that the inhibitor against enkephalinase will be highly effective for eliminating or minimizing the pain of such patients who feel chronic pain. In view of the disclosure in the "Showa Igakukai Zasshi" Vol. 39, No.5, pages 543 to 550 (1979), it is also expected that an enkephalinase-inhibitor will be useful as an aid for enhancing the acupuncture analgesia and morphine analgesia, and that such enkephalinase-inhibitor, even alone, will be effective to change the acupuncture-ineffective patients into the acupuncture-effective patients.
In an attempt to provide a new analgesic agent, therefore, we have extensively researched on the inhibitory activity of many known compounds against enkephalinase, the enzyme of degrading enkephalin. As a result, we have now found that 3-amino-2-hydroxy-4-phenylbutanoic acid and some related compounds thereof have the enkephalinase-inhibiting activity in vitro and, when tested in animals, exhibit the analgesic activity in vivo. Based on these our findings, we have completed this invention.
An object of this invention is to provide a new pharmaceutical composition which is useful as an analgesic agent or antinociceptive agent when used alone and which is useful to enhance the analgesic activity of morphine when it is administered in association with morphine. Another objects and utilities of this invention will be clear from the following descriptions.